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Abstract
All embryonic epithelia develop in relation to extracellular fluids, but the relationship of these fluids to epithelial and stem cell development is largely unexplored. Here we show that cerebrospinal fluid (CSF), which contacts all neuroepithelial progenitor cells at their apical membrane, stimulates proliferation and maintenance of neural progenitor cells in an age-dependent fashion. CSF taken from the rat lateral ventricle during neurogenesis dramatically stimulates progenitor proliferation, whereas CSF from earlier ages (E13, 14) or later ages (P6 or adult) shows more modest effects. Mass spectrometry and Western analysis identify many age-dependent changes in the CSF proteome, including a transient increase in IGF2 during peak neurogenesis that may relate to the changing effects of CSF on proliferation. Indeed, embryonic CSF activates the IGF 1 receptor and the AKT and the mitogen-activated protein kinase (MAPK) downstream signaling pathways. Further, neutralizing IGF2 in the CSF diminishes the CSF's stimulatory role in cortical progenitor cell proliferation, while supplementing basal media with IGF2 is sufficient to enhance proliferation in cortical explants and neural stem cells, suggesting that IGF2 released into the CSF plays an essential role in regulating the timing of proliferation of neuroepithelial progenitor cells of the cerebral cortex. Changing levels of secreted growth factors and other regulatory molecules, such as IGF2, in the CSF strongly suggests a role for the CSF as a vehicle for orchestrating cortical neurogenesis.
In this thesis, we have elucidated that embryonic CSF plays a fundamental, dynamic role in defining an endogenous niche for the survival and proliferation of cortical neural progenitors, and as a global regulator of neurogenesis—despite a more traditional view of the CSF as a fluid cushion that bathes the central nervous system, or as a passive sink for biomarkers of central nervous system function and pathology. Together, our findings show that the CSF proteome is a dynamic, active niche for neural stem cell and progenitor cell proliferation, survival, and maintenance and may represent an important therapeutic target.
